Physician-Scientist was a Pioneer in Medical Genetics,Down Syndrome and Aging Research

February 16, 2011 Charles J Epstein, MD, a leading contributor to the fields of human and medical genetics, died on Tuesday, February 15, at the age of 77. He passed away at his home in Tiburon, California after a protracted struggle with pancreatic cancer.

Dr. Epstein was a prolific scientist and educator who trained hundreds of doctors, scientists, and genetic counselors, and treated thousands of patients and parents faced with challenging situations related to chromosomal and genetic anomalies. He published more than 500 scholarly papers and authored and edited several books. He was an artist and craftsman and a lover of travel and culture. A private and modest man, Epstein eschewed the public eye, even when he was the victim of a mail bomb attack by Ted Kaczynski, the Unabomber.

Epstein was born on September 3, 1933 in Philadelphia, PA, the son of Jacob C Epstein and Frieda (Savransky) Epstein, Jewish immigrants from the Ukraine. Like his older brother, Herbert (Bob) and his younger brother Edwin, he went to Philadelphia's Central High School, where he excelled in academics, at track and field, and as a cellist.

Epstein went to Harvard College, where he met his wife and life partner, Lois Barth, on the steps of Radcliffe's Barnard Hall on a blind date in February 1952. Three months later he proposed to her, using a rolled-up cello string as a ring. He graduated summa cum laude with an A.B. in chemistry, in 1955, and entered Harvard Medical School with his wife-to-be in the fall of 1955. They were married in 1956, despite the urging of their parents to wait until graduation, and worked their way through medical school. He graduated magna cum laude and 1st in his class at HMS in 1959, and then interned at Harvard's Peter Bent Brigham hospital.

Epstein began his work in medical genetics – the application of genetics research to human care – in a fellowship with Arno Motulsky, one of the founders of medical genetics, at his Seattle lab. In his time there, Epstein worked to understand the nature of Werner's syndrome, a genetic disease which causes premature aging, and this pathway led him to his life's research work in understanding the biochemical basis behind the effects of chromosomal and genetic abnormalities.

After a research position at the National Institutes of Health, working under Christian Anfinsen, later a Nobel laureate, Epstein moved to San Francisco in 1967 where he joined the faculty of the University of California, San Francisco, as the chair of the medical genetics division in the department of pediatrics. He joined the department of biochemistry in 1970 and become a full professor of biochemistry and pediatrics in 1972. He was named director of UCSF’s human genetics program in 1997. He became a professor emeritus in 2005.

Epstein is best known in the research community for his contributions to the field of Down Syndrome research. People with Down Syndrome have a third copy of the 21st chromosome, and generally have impaired development, more rapid aging, and certain congenital heart defects. Epstein wanted to understand why the syndrome presented that way. He formed a seminal hypothesis in the 1970s – the "gene dosage effect hypothesis" – which posited that having an extra chromosome, and thus extra copies of genes, would result in the creation of a more than normal amount of specific proteins, which in turn would result in the manifestations of the syndrome. While initially dismissed by many, Epstein's hypothesis was proven correct and formed the basis for a broad array of medical genetic research around the world.

Doing laboratory research on Down syndrome was a difficult challenge which Epstein also tackled. Working with his wife, Dr. Lois Epstein, an expert on interferon, they established that the gene for interferon response was on chromosome 16 in mice, making it analogous to the human chromosome 21. Together, they produced the first mouse model to be used in Down Syndrome research, which they made freely available to researchers around the world. This work has been the basis for the huge advancement in the world's understanding of Down Syndrome and work towards treatments for that illness.

Epstein's work with Down Syndrome led him into the further research on cellular aging and the role of various enzymes, including superoxide dismutase, on the aging process.

Epstein received multiple awards and honors for his work, including the Allan Award, the McKusick Leadership Award, and the Weisman Award. He served as a leader to a broad range of professional groups, including as President of the American College of Medical Genetics, President and Board Director of the American Society of Human Genetics, President and Board Director of the American Board of Medical Genetics. He served as an editor on a wide number of professional journals, and as a member of a large number of government panels. For the last ten years of his life, he was an active participant in the formation of the Buck Institute for Age Research, as member and Chairman of the Scientific Advisory Board, and as a member and chairman of the Board of Trustees.

Epstein's work and family life was interrupted in 1993 when he was the recipient of the first mail bomb sent by Ted Kaczynski, the Unabomber, after a long hiatus. The explosion caused a great deal of harm, including substantial internal injuries, loss of several fingers, and a partial loss of hearing. The crisis caused a huge outpouring of support from his friends and family, and Epstein received thousands of letters from people whose life he had touched, directly and indirectly.

Epstein was an artist who loved to play the violoncello, and played in many orchestras, including, most recently, the orchestra of the Bohemian Club. He and his wife also became experts at dollhouse construction, creating a large number of intricate and fully decorated structures that they gave to their grandchildren and other family members.

A lover of travel, Epstein and his wife visited most of the major countries of the world, for both work and for pleasure. On their travels, they assembled a collection of musical instruments that has been loaned to museums for special exhibitions.

Epstein was a scientist, physician, musician, husband, father, brother, teacher, and friend to many. He was a humanist who believed in the value of each every human being. His approach towards life, and the adversity that sometimes comes with it, are perhaps best summed up in his words of advice, when asked the by parents of a Down Syndrome child what they should do with their new baby. He said, "Love your child! Treat him or her as normally as possible and as a cherished member of the family…do the best that you can and try to take each day as it comes."

Epstein is survived by his wife, Lois, his children, David Epstein and Abigail Lewis of Ossining, New York, Jonathan Epstein, Teresa Hegg and Andrea Bruno of San Francisco, California, Paul Epstein and Jennifer Traub of Piedmont, California, and Joanna Epstein and Dan Bornstein of San Francisco, California. He is survived by six grandchildren -- Jeffrey, Kendra, Jacqueline and Genevieve Epstein, and Violet and Simon Traub-Epstein – and his siblings Herbert and Jean Epstein of Watertown, Massachusetts, and Edwin and Sandra Epstein of Berkeley, California.

A funeral will be held on Sunday, February 20, at 1pm, at Congregation Kol Shofar, 215 Blackfield Drive, Tiburon, CA, 94920. Rabbi David White will officiate. Epstein will be interred at Mount Tamalpais Cemetery in San Rafael, California. Sinai Memorial Chapel in San Francisco is handling the funeral arrangements. For more information on the service, call 415-350-7887.

Dr. Epstein's family has asked that, in lieu of flowers, donations be made in his memory to support the Buck Institute on Age Research, 8001 Redwood Boulevard, Novato, CA 94945 (www.buckinstitute.org).